The molecular mechanisms underlying neuronal and axonal pathology in neurodegenerative and inflammatory diseases including multiple sclerosis remain unclear. However, increasing evidence indicates that ion dyshomeostasis, particularly disruption of calcium balance, may play a pivotal role in neuronal and axonal injury. The purpose of these studies is to examine how the deficiency in plasma membrane calcium ATPase isoform 2 (PMCA2), a major pump involved in neuronal calcium extrusion, leads to dysfunction and death of spinal cord neurons. It is hypothesized that the lack of PMCA2 causes neuronal injury due to induction of calpain, a calcium-activated protease which, in turn, degrades cytoskeletal proteins and especially non-phosphoryated neurofilaments. Furthermore, it is proposed that PMCA2 deficiency leads to mitochondrial dysfunction and apoptosis. This hypothesis is investigated by use of a PMCA inhibitor in pure spinal cord neuronal cultures as well as PMCA2-null mice, which exhibit motor deficits due to loss of spinal cord motor neurons. [unreadable] [unreadable] [unreadable]